Background Patient-reported outcomes (PROs) are essential for assessing symptomatic adverse events (AEs) from a patient perspective, which significantly impact the quality of life and clinical outcomes in patients with glioma. However, no validated patient-reported outcome measures (PROMs) exist to quantify symptomatic AEs in adult-type diffuse gliomas. Methods The study was conducted in two parts. First, we developed a customised Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) scale for adult-type diffuse gliomas using the Simplified Chinese PRO-CTCAE® item library, informed by initial item screening, patient pilot testing, and a two-round Delphi survey. Delphi experts were recruited through the National Glioma Multidisciplinary Team (MDT) Alliance (NGMA) and invited by email in June 2022 (1st round) and August 2022 (2nd round). We subsequently conducted a multicentre, prospective, observational cohort study (VERONICA) at 13 glioma treatment centres in China between September 2022 and March 2025. Eligible participants were adults aged 18 years or older with a diagnosis of adult-type diffuse glioma, who were able to understand and complete the questionnaires; patients with severe cognitive impairment, severe language dysfunction, or other conditions precluding questionnaire completion were excluded. The primary outcome was the psychometric performance of the customised PRO-CTCAE scale, including test-retest reliability, convergent validity, known-groups validity, and responsiveness, evaluated longitudinally across repeated study visits. VERONICA is registered with ClinicalTrials.gov, NCT05486923. Findings For the Delphi survey, all seven invited experts from six centres participated in 1st round (response rate 100·0%), with moderate agreement in symptom rankings (Kendall's W = 0·415; p < 0·001). In 2nd round, 16 of 20 invited experts from 14 centres participated (response rate 80·0%), with consistent agreement in expert ratings (Kendall's W = 0·351; p < 0·001). The final version of the customised PRO-CTCAE scale comprised 53 items covering 31 symptoms, together with one open-ended free-text item. For VERONICA, 450 participants were enrolled across 13 glioma treatment centres. Mean age was 49·1 years (SD 12·8), and the mean Karnofsky Performance Status (KPS) at baseline (Visit 2) was 72·2 (SD 17·1). 424 provided data eligible for at least one prespecified psychometric analysis. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] ≥0·70 for 47 of 53 items). Convergent validity was supported by correlations in the expected direction with matched European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) domains, with predominantly moderate-to-strong associations (25 items with r ≥ 0·50). Known-groups validity was supported by discrimination between KPS <70 and ≥70 (Cohen's d ≥ 0·20 for 49 of 53 items; p < 0·05 for 43 of 49 items). In Global Impression of Change (GIC)-anchored responsiveness analyses, 37 items showed standardised response means (SRMs) ≥0·20 among participants reporting worsened overall status. Interpretation The customised PRO-CTCAE scale showed robust psychometric performance for adult-type diffuse gliomas. Remote, longitudinal administration supports low-burden quantification of patient-reported symptomatic AEs in clinical trials and routine neuro-oncology practice. Future work should assess implementation in routine care and clinical trials, and extend translation, cultural adaptation, and validation across different languages. Funding Beijing Medical Award Foundation; Shanghai Municipal Health Commission; Department of Science and Technology of Ningxia Hui Autonomous Region; Huashan Hospital, Fudan University (Clinical Research Project).

Glioblastoma (GBM) is highly heterogeneous, complicating effective tumor elimination. Among GBM subtypes, the mesenchymal (MES) variant is associated with the poorest prognosis. Notably, macrophage infiltration is significantly higher in MES GBM. However, the regulatory networks underlying this distinct MES GBM microenvironment remain poorly understood. Here, we demonstrate that MES glioblastoma stem cells (GSCs) exhibit a preferential expression and secretion of the protein LY96. Mechanistically, MES GSCs engage an autocrine LY96-TNFRSF1B signaling axis that activates NF-κB, thereby promoting their proliferation, self-renewal, and maintenance of the MES state. Inhibition of LY96 in vivo suppresses GBM growth and prolongs survival in animal models. Additionally, LY96 acts in a paracrine manner on tumor-associated macrophages (TAMs), driving their polarization toward a MES-like state. Collectively, our findings identify LY96 as a key regulator of the MES state in GSCs and a driver of MES-like polarization in TAMs. Therapeutic strategies targeting LY96 and its downstream effectors may improve GBM treatment outcomes.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, and radiotherapy is a key treatment option. However, glioblastoma stem cells (GSCs) can develop resistance to radiotherapy through metabolic reprogramming, which often results in tumor recurrence. Here we found that glycolytic enzyme phosphoglycerate kinase 1 (PGK1) was phosphorylated at threonine 8 (T8) by ataxia telangiectasia mutated (ATM) upon irradiation (IR), leading to enhanced binding of PGK1 to phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme for the serine synthesis pathway (SSP). PGK1 subsequently functioned as a protein kinase to phosphorylate PHGDH at T60, which resulted in enhanced PHGDH enzymatic activity and increased serine synthesis to fuel the production of S-adenosylmethionine (SAM). Increased SAM then promoted the levels of histone H3K36 trimethylation (H3K36me3) to recruit RAD51 to engage homologous recombination (HR)-mediated DNA damage repair to confer resistance of GSCs to IR. Importantly, both inhibiting PHGDH T60 phosphorylation and suppressing its enzymatic activity sensitized GSCs to IR, inhibited growth of orthotopich xenografts, and prolonged survival of tumor-bearing mice. Furthermore, clinical analysis indicated that phosphorylation levels at both PHGDH T60 and PGK1 T8 corresponded closely with the poor prognosis of GBM patients. This study revealed an ATM-PGK1-PHGDH signaling axis that promoted serine synthesis to confer resistance of GSCs to IR, and suggested that targeting PHGDH may serve as a potential strategy to overcome radioresistance in GBM.

Temozolomide (TMZ) resistance in glioblastoma (GBM) remains a substantial clinical challenge. Targeting glioma stem cells (GSCs) represents a promising strategy to overcome chemoresistance and tumor recurrence. In this study, we found that GSCs maintain chemoresistance by increasing pentose phosphate pathway (PPP) flux compared with differentiated tumor cells. Following TMZ treatment, the activity of glucose-6-phosphate isomerase (GPI), a key glycolytic enzyme that catalyzes the conversion of glucose-6-phosphate to fructose-6-phosphate, was significantly suppressed in GSCs. Mechanistically, Ataxia Telangiectasia Mutated (ATM), activated by TMZ-induced DNA damage, phosphorylates polo-like kinase 1 (PLK1), promoting its nuclear export. PLK1 subsequently phosphorylates GPI at T215, leading to suppression of GPI activity. Targeting the ATM/PLK1/GPI axis through combinational treatment with rigosertib may therefore represent a therapeutic strategy. Moreover, PLK1 expression and GPI pT215 levels may serve as potential candidate markers for GBM. Collectively, activation of the ATM/PLK1/GPI axis plays a critical role in regulating PPP flux and TMZ resistance in GSCs.

Glioblastoma stem cells (GSCs) are refractory to first-line treatment in the clinic, which includes irradiation (IR) and temozolomide (TMZ). Here we find that disrupting stress granules (SGs) sensitizes GSCs to IR/TMZ through ferroptosis. The profiling of SG proteins reveals the recruitment of iron-related proteins including ferritin. Mechanistically, G3BP1, an SG core protein, directly interacts with ferritin light chain in an IR/TMZ-induced G3BP1 methionine-333 oxidation-dependent manner. This interaction facilitates recruiting and sequestering ferritin into SGs, thereby restricting ferroptosis by limiting Fe2+ content in the labile iron pool and preventing ferritinophagy. Disrupting G3BP1 and ferritin light chain binding using a screened small molecule, ciwujianoside C3, mitigates the restriction of SGs on ferroptosis, and resensitizes GSCs to IR/TMZ in both in vitro and animal models. These findings unveil a negative regulation of SGs on ferroptosis, and reveal a promising strategy to disrupt the SG-ferroptosis axis for treating glioblastomas and probably other types of cancer.

Meningioma is the most common central nervous system tumor and high-grade tumors frequently show progressive growth or recurrence, posing substantial therapeutic challenges. However, the lack of effective chemotherapy and targeted therapies contributes to poor prognoses in patients with high-grade disease. In this study, we evaluated KRT18 expression in meningiomas and examined its correlation with patient prognosis using RNA sequencing and immunofluorescence staining. The oncogenic role of KRT18 in high-grade meningioma was further investigated using IOMM-Lee and CH157-MN cells, xenograft mouse models, and paraffin-embedded meningioma tissue sections. Finally, small-molecule inhibitors targeting KRT18-related mechanisms were explored. Analysis of clinical specimens across different meningioma grades demonstrated that KRT18 overexpression is associated with more advanced clinical features and poorer prognosis. Functional studies showed that KRT18 promotes meningioma cell proliferation and facilitates cell cycle progression by activating the PI3K/AKT signaling pathway. Mechanistically, KRT18 interacted with LDHA, an upstream regulator of PI3K/AKT signaling, and enhanced LDHA stability via inhibition of ubiquitination, which drives oncogenic growth by activating glycolysis and the PI3K/AKT signaling pathway. These findings were corroborated in a xenograft model. Finally, Fluvastatin was identified as a novel inhibitor that specifically targets the interaction between KRT18 and LDHA, thereby inhibiting meningioma proliferation by suppressing glycolysis and PI3K/AKT signaling. Collectively, these findings indicate that KRT18 serves as a potential diagnostic, prognostic, aggressiveness-related, and potential grading biomarker. It also functions as an oncogene by activating glycolysis and the PI3K/AKT signaling pathway through interaction with LDHA. Additionally, Fluvastatin is identified as a candidate for drug repurposing in high-grade meningioma.

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide, with secondary injury recognized as a critical therapeutic target. Quercetin (QR), a natural flavonoid, exerts antioxidant and anti-inflammatory effects by modulating the Nrf2-Keap1 pathway and shows neuroprotective potential in various neurological disorders. In this study, network pharmacology analysis identified 496 overlapping targets of QR and TBI, further highlighting the pivotal role of the Nrf2-Keap1 pathway in TBI treatment. However, the poor blood-brain barrier (BBB) permeability and low bioavailability of QR hinder effective brain-targeted delivery and limit its clinical translation. To address these challenges, we developed CAQK peptide-modified, reactive oxygen species (ROS)-responsive nanoparticles (C-PPS/Q), using PPS120 as the core for targeted QR delivery. C-PPS/Q exhibited ROS-triggered QR release, significantly enhanced HT22 cell uptake in vitro, reduced ROS levels and apoptosis. In a TBI mouse model, C-PPS/Q specifically accumulated at the lesion site, prolonged the half-life of QR, demonstrated excellent biocompatibility, preserved BBB integrity, attenuated neuroinflammation, inhibited aberrant Nrf2-Keap1 pathway activation, and markedly improved neurological function. Collectively, C-PPS/Q nanoparticles effectively mitigate secondary brain injury after TBI and represent a promising brain-targeted therapeutic strategy for TBI management.

Background3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme in cholesterol metabolism, remains underexplored in meningioma. Additionally, the therapeutic potential of Brusatol (Bru), a triterpene lactone compound with anticancer properties, has yet to be systematically evaluated. This research investigates Bru’s efficacy in meningioma treatment and HMGCR-related mechanisms.MethodsIC50 was determined using CCK-8 assay. Proliferation, apoptosis, migration, and invasion were assessed through colony formation, EdU, Annexin V/PI staining, Scratch, and Transwell assays, respectively. Cholesterol levels were measured with an assay kit and Filipin III probes. Key pathways and potential meningioma-specific marker were identified via multi-omics with GO/KEGG analyses and bioinformatic analyses. Protein expression was detected via Western blot analysis, and a mouse model of meningioma was employed to evaluate the efficacy of Bru.ResultsBru inhibited the proliferation, migration, and invasion of meningioma cells, induced apoptosis, and reduced cholesterol accumulation. Proteomic, transcriptomic, and bioinformatic analyses, along with molecular docking, revealed that Bru targeted HMGCR to restrict cholesterol biosynthesis and inhibit the PI3K/AKT signalling pathway. These findings were validated through a series of experiments, including surface plasmon resonance assay, HMGCR knockdown and overexpression, and rescue experiments where HMGCR knockdown or Bru treatment was reversed with an Akt activator SC79. In vivo experiments indicated that Bru effectively suppresses tumour progression, with no significant toxicity observed under the current experimental conditions.ConclusionThese findings demonstrate that Brusatol suppresses meningioma progression by inhibiting of HMGCR and the PI3K/AKT signaling pathway.

Patients with temporal gliomas often experience severe cognitive impairment after surgery, despite the attention given to the protection of cognitive structures during surgery. Connectomics provides a unified, network-based view dedicated to mapping and understanding the structural and functional topology of the human brain. This study aims to elucidate the characteristics of temporal glioma invasion into brain networks (including the salience network, central executive network, default mode network, dorsal attention network, and ventral attention network) and summarize the clinical effectiveness and practical experience in protecting cognitive function under the guidance of connectomics. First, connectomics was utilized to construct personalized brain functional networks for each patient, enabling a retrospective analysis of the invasion characteristics of 53 temporal gliomas for both functional structures and brain networks. The therapeutic effects of connectomics-optimized surgical programs (the experimental group) and traditional surgical strategies (the control group) on patients’ brain structures and cognitive functions were subsequently compared in 29 patients with temporal gliomas and 18 patients with left temporal gliomas. In 52/53 patients (98.11

Purpose The exact mechanisms underlying the distinct neurological outcomes between Traumatic Brain Injury (TBI) and Hemorrhagic Stroke (HS) remain unclear. Our objective is to assess distinct features of neurologic state between comatose patients with TBI and HS during the stage of acute disorder of consciousness (aDoC) and to identify the correlation of neurologic features with prognosis. Methods Data were analyzed from TBI and HS patients examined by positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) simultaneously. Primary clinical outcomes consisted of the state of consciousness and neurological prognosis. The regional neural activity was assessed by the amplitude of fractional low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) on rs-fMRI scans. The standardized uptake value (SUV) on PET scans quantified neural metabolism. Functional connectivity (FC) and graph theoretic approach (GTA) were employed to compare the FC patterns between TBI and HS. Correlations of PET/rs-fMRI indicators with the prognosis of HS and TBI were identified. Results Muti-modal PET/rs-fMRI analysis showed more active local neurological state in TBI patients than HS patients, specifically in the right precentral gyrus (PreCG.R), right postcentral gyrus (PoCG.R), right superior temporal gyrus (STG.R) and right middle temporal gyrus (MTG.R). TBI patients demonstrated significantly higher clustering coefficient and nodal efficiency of the sensorimotor network (SMN) along with lower connectivity and network efficiency in the default network (DMN) compared to HS patients. PET/rs-fMRI indicators significantly correlated with the neurological prognosis of TBI and HS. Conclusions This study elucidated the underlying mechanisms contributing to the distinct neurologic prognosis between comatose TBI and HS patients, and may contribute to the development of early targeted intervention strategies for specific diseases.

Table S8. IHC scores of 95 GBM samples

Table S2. Logistic regression analysis from GLASS database

Background: Surgical intervention, complemented by radiotherapy and chemotherapy with temozolomide, constitutes the conventional treatment protocol for patients with newly diagnosed grade 4 glioma. We have conducted a research to evaluate the efficacy and safety of an integrated treatment regimen that incorporates tumor-treating fields with concurrent chemoradiotherapy. Methods: This retrospective research analyzed the clinical data of 39 adults who were newly diagnosed with World Health Organization (WHO) grade 4 gliomas at the First Affiliated Hospital of Nanjing Medical University, between February 2022 and April 2023. Each participant received a concurrent treatment regimen consisting of temozolomide (75 mg/m 2 daily), tumor-treating fields (200 kHz), and brain irradiation (60 Gy delivered in 30 fractions). Maintenance treatment comprised ongoing temozolomide and tumor-treating fields. Adverse events were documented in accordance with the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0) and specific grading criteria for dermatological adverse events associated with tumor-treating fields. Results: Among the 39 enrolled patients, disease progression was observed in 22 individuals (56.4%), with a median progression-free survival (PFS) of 14.2 months (95% confidence interval [CI]: 13.1-14.3 months). The median overall survival (OS) was 18.2 months (95% CI: 17.3 months to not reached). Patients diagnosed with glioblastoma had a median PFS of 13.1 months (95% CI: 12.9-14.2 months) and a median OS of 18.2 months (95% CI: 17.3 months to not reached). In contrast, patients diagnosed with astrocytoma had a median PFS of 14.3 months (95% CI: 12.8 months to not reached) and a median OS of 17.0 months (95% CI: 10.6 months to not reached). Twenty-five patients (64.1%) experienced dermatological adverse events, and 30 (77.0%) experienced mild hematological adverse reactions related to chemoradiotherapy. Conclusion: The application of tumor-treating fields concurrent with post-surgery chemoradiotherapy is both safe and effective for treating patients with newly diagnosed WHO grade 4 gliomas, exhibiting only limited toxicity.

Supplementary Figures and Figure legends

Table S1. Oligos used in this study

Table S5. GSVA scores for GBM cells

Preoperative assessment of World Health Organization (WHO) meningioma grading and Ki-67 expression is crucial for treatment strategies. We aimed to develop a fully automated attention-based deep learning network to predict WHO meningioma grading and Ki-67 expression. This retrospective study included 952 meningioma patients, divided into training (n = 542), internal validation (n = 96), and external test sets (n = 314). For each task, clinical, radiomics, and deep learning models were compared. We used no-new-Unet (nn-Unet) models to construct the segmentation network, followed by four classification models using ResNet50 or Swin Transformer architectures with 2D or 2.5D input strategies. All deep learning models incorporated attention mechanisms. Both the segmentation and 2.5D classification models demonstrated robust performance on the external test set. The segmentation network achieved Dice coefficients of 0.98 (0.97–0.99) and 0.87 (0.83–0.91) for brain parenchyma and tumour segmentation. For predicting meningioma grade, the 2.5D ResNet50 achieved the highest area under the curve (AUC) of 0.90 (0.85–0.93), significantly outperforming the clinical (AUC = 0.77 [0.70–0.83], p < 0.001) and radiomics models (AUC = 0.80 [0.75–0.85], p < 0.001). For Ki-67 expression prediction, the 2.5D Swin Transformer achieved the highest AUC of 0.89 (0.85–0.93), outperforming both the clinical (AUC = 0.76 [0.71–0.81], p < 0.001) and radiomics models (AUC = 0.82 [0.77–0.86], p = 0.002). Our automated deep learning network demonstrated superior performance. This novel network could support more precise treatment planning for meningioma patients. Question Can artificial intelligence accurately assess meningioma WHO grade and Ki-67 expression from preoperative MRI to guide personalised treatment and follow-up strategies? Findings The attention-enhanced nn-Unet segmentation achieved high accuracy, while 2.5D deep learning models with attention mechanisms achieved accurate prediction of grades and Ki-67. Clinical relevance Our fully automated 2.5D deep learning model, enhanced with attention mechanisms, accurately predicts WHO grades and Ki-67 expression levels in meningiomas, offering a robust, objective, and non-invasive solution to support clinical diagnosis and optimise treatment planning.

We introduce LetsACT (Light-Electron-Transcriptome synergistic ACTomography), a multimodal integration platform that overcomes the limitations of single-modality data acquisition and analysis of human brain cells while synergistically leveraging the strengths of each modality. Our approach enables the rapid sample preparation, cell injection, imaging, and multimodal integration of large-scale human neuronal datasets at single-cell resolution. By generating initial laser-scanning-microscopy based optical reconstruction of neuron morphologies followed by refining them using electron-microscopy derived morphological priors, we have assembled one of the largest human cortical morphology datasets to date: 8,398 neurons from 58 donors, with high cortical coverage. This platform is then applied to studying morphological impact of tumor infiltration. Pyramidal neurons in glioma-infiltrated tissues display clear volume shrinkage in somas and branches, tapering from the soma to nearby dendritic compartments. By integrating these morphological variations with spatial and bulk transcriptomic profiles, we find that glioblastoma tissues exhibit dysregulation of 15.29% of genes, including overexpression of TERT, whereas infiltrated tissues show 7.74% gene dysregulation, characterized by overexpression of tumor suppressors such as CDKN2A and TP53. Our analysis implies that pyramidal neurons observed in these infiltrated tissues may involve an active defense instead of undergoing passive apoptosis. Our finding also indicates that LetsACT establishes a valuable resource for the large-scale, comprehensive morpho-genetic analysis of human tissues.